Synthesis of glutamic acid and salts thereof



States SYNTHESIS OF GLUTAMIC ACID AND SALTS THEREOF No Drawing. Application April 23, 1957 Serial No. 654,613

'14 Claims. (Cl. 260-533) This invention relates to an improved method for synthesizing glutarnic acid and salts thereof. This application is a continuation-in-part of application Serial No. 435,096, now U.S. Patent No. 2,791,606.

Monosodium glutamate has attained wide commercial acceptance as a cooking aid since it has been found to enhance the natural flavor and taste of various foods without itself contributing any noticeable odor or taste to the food.

The monosodium salt having value for accenting food flavors is derived from the active levoratory form of the acid. This latter substance occurs naturally in vegetable protein hydrolyzates from which it can be extracted. However, the selective extraction of the l-glutamic acid is an expensive process and the cost of the extracted acid is, therefore, quite high.

Various organic syntheses of glutamic acid are known, including procedures utilizing, as starting materials, relatively expensive malonic acid derivatives such as aminomalonic esters, benzoylaminomalonic esters, aceto-aminomalonic ester and phthalimidomalonic ester. These processes are tedious and result in low yields of a racemic product, i.e., a mixture of dand l-glutamic acid in which the l-glutamic acid is present in an amount of about 50%. To find a market for use as a flavor enhancing agent with the sodium salt of protein hydrolyzate extracts in which the active l-glutamic acid is not admixed with the inactive dextro-rotary form, the sodium salt derived from racemic glutamic acid containing only about 50% by weight of the active levoratory form, must sell at about half the price of the salt of the protein hydrolyzate extracts. This is not feasible economically since the cost of synthesizing the acid by the known methods is relatively high.

One object of the present invention is to provide a new and improved method of synthesizing glutamic acid utilizing comparatively inexpensive starting materials and reagents and involving a series of reactions which are readily controllable.

Another object is to provide a method of synthesizing I sodium glutamate which can be profitably marketed at a price considerably less than that of the sodium salt of glutamic acid synthesized by the procedures heretofor available to the art.

These and other objects are achieved by utilizing, as

starting material for the synthesis, cyclopentadiene obtained by depolymerization of readily available and inexpensive polymers of cyclopentadiene such as the dimer, dicyclopentadiene, which is easily depolymerized to the active monomer by distillation at atmospheric pressure.

In a preferred embodiment of the invention, the dicyclopentadiene is depolymerized to cyclopentadiene by distillation, the monomer is treated with gaseous hydroatent O drochloride which, on treatment with aqueous sodium hydroxide, yields a mixture of substantially equal proportions of the sodium salts of the active l-glutamic acid and inactive d-glutamic acid.

In a modification of the procedure outlined, the 2- chloroor 2-bromo-cyclopentene-1 is converted directly to 2-amino-cyclopentene-1 by treatment with an excess of an aqueous solution of ammonia, and the amino group is protected during oxidation and opening of the ring by intermediate acylation, whereby the two hydrogen atoms of the amino group are replaced by lower acyl (2-4 carbons) radicals. Oxidation of the diacylated amino cyclopentene-l in the presence of sulfuric acid which, on heating in the presence of the sulfuric acid, is converted to glutamic acid sulfate, the latter being in turn converted to the monosodium glutamate on treatment with aqueous sodium hydroxide. In this modified procedure oxidation of the diacylated amino cyclopentene-l and conversion of the resulting diacylated glutamic acid to the sulfate are preferably carried out in the same reaction vessel, without intermediate isolation of the oxidation product.

The following examples are given to illustrate the invention, it being understood that these examples are not intended to be limitative with respect to the specific details thereof.

Example I drogen chloride gas is bubbled through the cooled liquid at a temperature below 25 0, usually at -30 C. to -35 C., until 2-chlorocyclopentene-l is produced. About 1128 lbs. of the latter are then treated with an excess of potassium permanganate and sulfuric acid preferably introduced into the warmed solution concurrently and in the form of thin streams, with stirring of the mass. This oxidizing treatment opens the ring, with production of 2-chloroglutaric acid. About 1600 lbs. of the 2-chloroglutaric acid are autoclaved in 1300 lbs.

" of water containing 850 lbs. of ammonia and 1300 lbs.

gen chloride or bromide to produce 2-chloroor 2-bromocyclopentene-l, the cyclopentene-l is oxidized, with cleavage of the ring, to 2-chloroglutaric or 2-bromoglutaric acid which, on ammonolysis, yields ammonium glutamate, the latter being converted to glutamic acid hyof CO at a temperature of 50 C. and under a pressure of 50p.s.i. for 12 hours to produce 1300 lbs. of arnm0-- nium glutamate. The ammonium glutamate is treated with hydrochloric acid, the hydrochloride being formed,

and an aqueous solution of sodium hydroxide is added to adjust the pH to the alkaline side and produce the desired sodium glutamate, which may be recovered from the solution by evaporation of the water, together .with sodium chloride, the presence of which latter may be desirable in the condiment.

Instead of potassium permanganate, other similar oxidizing agents may be used, such as perrhenates, vanadates, chromates, ferrates or periodates. Instead of oxidizing the 2-halocyclopentene-1 in aqueous medium, a

catalytic vapor phase process using air as the oxidant may be employed.

Other variations may be made in the procedure of Example 1. Thus, the 2-chloroglutaric acid may be aminated by autoclaving in from 1300 to 4250 lbs. of water at 35 C. to 65 C. and under a pressure of from Also, for the amination, from 850 to 0 to 200 p.s.i.

1250 lbs. of ammonia and from 1300 to 2640 lbs. of 7 CO may be used in the solution. scribed has the advantage that only a relatively small amount of ammonia is required to prevent the formation of polyalkylated by-products, i.e., only about 4 to 7 mols. The pH at which the amination is conducted under the conditions described prevents hydrolysis of the 2-chloro-' The procedure deglutaric acid to 2-hydroxyglutaric acid and, in addition,

under the described operating conditions, carbamate groups are formed which inhibit the formation of polyalkylated ammonium salts thus avoiding another of the major disadvantages of priijf syntheses.

Example II About 1220lbs. of 73% dicyclopentadiene are charged into a still and distilled as in Example 1'. Hydrogen chloride gas is bubbled into 792 lbs. of the cyclopentadiene recovered in the distillation untilj 2 -chlorocyclopentene-1 is produced. The Z-chlorocyclopentene-l is converted directly to the Z-amino cyclopentene-l by autoclaving 1128 lbs. of the chloro-derivative with 5000 lbs. of 26% aqueous ammonia for 8 hours at 120 C. and 70 p.s.i. About 750 lbs, of the Z-amino-cyclopentene-l thus obtained are acetylated by treatment with excess acetyl chloride, and the diacetylated product, Z-(diacetylamino) cyclopentene-l, is oxidized by treatment with potassium permanganate in the presence of sulfuric acid, the oxidizing agent and catalyst being introduced into the mass comprising the diacetylated material concurrently in the form of thin streams, with continuous stirring of the mass to insure uniform distribution of the permanganate and catalyst therethrough. The mass is then heated for 5 to IOminutes to efiect conversion of the diacetyl glutamic acid resulting from the oxidation, to glutamic acid, sulfate, after which sufiicient aqueous sodium hydroxide is added to convert the sulfate to sodium glutamate.

The conditions may be varied. Thus, the 2 -chlorocyclopentene-l may be autoclaved, with an aminating;

solution consisting of from 5000 to 10,000 lbs. of 26% to 30% aqueous ammonia for 8 to 12 hours at 120 C. 117 C. and a pressure of from 70 to 200 psi. Also, instead of oxidizing the diacetylaminocyclopentene-1 by means of potassium permanganate in the presence of sulfuric acid, from 30% to 60% nitric acid may be used as the oxidizing agent, and the glutamic acid hydronitrate thus produced may be treated with aqueous sodium hydroxide to produce the monosodium, glutamate.

Oxidizing acids other than nitric acid may be used, such as perchloric, periodic or selenic acid.

The sodium glutamate (consisting of a mixture of substantially equal proportions of the l and d-forms) is obtained in good yield as a white or almost White crystalline powder which may be added to meat and other food stuflfs to enhance the natural food flavor. The overall cost of producing the sodium glutamate by the present procedure is comparatively low so that the product can be marketed at a price competitive with the protein hydrolyzate extracts consisting essentially of the active levoratory form of the acid. 7

Instead of obtaining the cyclopentadiene by distillation of the dimer, other polymers of cyclopentadiene may be. depolymerized to the monomer by distillation, such .as the trimer, tetramer, etc.

It will be understood that when it is desired to produce glutamic acid as such as for any purpose, as for medicinal use, the free amino acid may be obtained directly or recoverd from the salt by neutralization of the latter. The hydrochloride may also be used as such, for instance in the treatment of achlorhydria and hypochlorhydria. Likewise, when other alkali metal salts of glutamic acid are desired, these may be obtained by treating the hydrochloride with an aqueous solution of the appropriate alkali metal hydroxide, or alkaline earth metal hydroxide, such as potassium, lithium or calcium hydrfoxide.

It will also be apparent that this invention provides a novel method for producing Z-haloglutaric acids, 2

monoacyl and 2-diacylarnino-1,5 dicarboxylic acids, 2- monoacyland Z-diacylaminocyclopentene-1.

Since the variations in details mentioned herein, and others, may be made within the scope of the disclosure, and without departing from the spirit and scope of the invention, it is to be understood. that it is not intended to limit the invention except. as defined in the appended claims.

What is claimed is:

1.. In. a method for producing glutamic acid sulfate, the steps comprising distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of-hydrogen chloride and hydrogen bromide until the corresponding Z-halo-cyclopentene-l is produced, treating the cyclopentenel with excess ammonia to obtain Z-aminocyclopentene-l, reacting the latter with an acyl chloride in which the acyl radical contains from 2 to 4 carbon atoms, oxidizing the resulting 2- diacylaminocyclopentene l to Z-diacylglutamic acid, and heating the latter in the presence of sulfuric acid to convert it to glutamic acid sulfate.

2. In a method of producing glutamicacid, the steps comprising distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of hydrogen chloride and hydrogen bromide until the corresponding 2-halo-cyclopentene-l is produced, treating the 2-halo-cyclopentene-1 with excess ammonia, to form Z-aminocyclopentene-l, reacting the latter with an acyl chloride the acyl radical of which contains from, 2 to 4 carbon atoms to produce the 2-diacyl amino-cyclopentene-l, oxidizing the latter to diacyl-.

glutamic acid by treating it with. potassium permanganate the presence of sulfuric acid, heating the mass resulting from the. oxidation, without isolation of the diacylglutamic acid therefrom, to convert the diacyl glutamic acid to glutamic acid sulfate, and covering the sulfate to the free glutamic acid by neutralization.

3. 'In a method of producing alkali metal or alkaline earth metal salts of glutamic acid the steps comprising distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with gaseous hydrogen chloride until 2-chloro-cyclopentene-l is produced, treating the Z-chloro-cyclopentene-l with eX- cess ammonia to form Z-amino-cyclopentene-l, reacting the latter with an acyl chloride the acyl radical of which contains from 2 to 4 carbon atoms, oxidizing the resulting 2-diacylamino-cyclopentene-1 to diacylglutamic acid by treating it with excess potassium permanganate in the presence of sulfuric acid, heating the oxidation mass, without isolation of the diacylglutamic acid therefrom, to convert the latter to glutamic acid sulfate, and treating the sulfate with an aqueous solution of a base selected from the group consisting of alkali metal and alkaline earth metal hydroxides to obtain the corresponding alkali metal or alkaline earth metal salt of glutamic acid.

4. In a method for producing a sodium salt of glutamic acid, the steps comprising distilling dicyclopentadiene to obtain the monomer cyclopentadiene, treating the monomer with gaseous hydrogen chloride until 2-chlorocyclopentene-l is produced, converting the'latter to Z-aminocyclopentene-l by treating it with an excess of an aqueous solution of ammonia, reacting the Z-aminocyclopentene-l with an acyl chloride the acyl radical of which contains from 2 to 4 carbon atoms, oxidizing the resulting 2 -diacylamino-cyclopentene-l to diacylglutarnic acid by treating it,with,potassiumpermanganate in the presence of sulfuric acid, heating the oxidation mass, without isolation of the diacylglutamic. acid therefrom, to convert the diacylated acid to glutamic acid sulfate, and treating the acid sulfate with aqueous sodium hydroxide to produce sodium glutamate. I

5. A method according to claim 4, characterized in that the, Z-aminocyclopentene-l is reacted with acetyl chloride.

6. 'In a method for producing a sodium salt of glutamic acid, the steps comprising distilling dicyclopentadiene to obtain the monomer cyclopentadiene, treating the monomer with gaseous hydrogen bromide until 2-bromocyclopentene-l is produced, converting the latter to 2- aminocyclopentene-l by treating it with an excess of an aqueous solution of ammonia, reacting the 2-aminocyclopentene-l with an acyl halide the acyl radical of which contains from 2 to 4 carbon atoms, oxidizing the resulting 2-diacylaminocyclopentene-1 to diacylglutamic acid by treating it with potassium permanganate in the presence of sulfuric acid, heating the oxidation mass, without isolation of the diacylglutamic acid therefrom, to convert the diacylated acid to glutamic acid sulfate, and treating the acid sulfate with aqueous sodium hydroxide to produce sodium glutamate.

7. A method according to claim 6, characterized in that the 2-aminocyclopentene-1 is reacted with acetyl chloride.

8. In a method for producing glutamic acid, the steps comprising distilling a polymer of cyclopentadiene to obtain the monomer therefrom, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of hydrogen chloride and hydrogen bromide until the corresponding 2-halocyclopentene-l is produced, converting the latter to Z-aminocyclopentene-l by treating it with an excess of an aqueous solution of ammonia, reacting the Z-aminocyclopentene-l with an acyl chloride in which the acyl radical contains from 2 to 4 carbon atoms, oxidizing the resulting 2-diacylaminocyclopentene-l to diacylglutamic acid by treating it with excess 30% to 60% nitric acid, and deacylating the oxidation product to obtain the free glutamic acid.

9. In a method for producing alkali metal and alkaline earth metal salts of glutamic acid, the steps comprising distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of hydrogen chloride and hydrogen bromide until the corresponding 2-halo-cyclopentene-1 is produced, converting the latter to 2-aminocyclopentene-1 by treating it with an excess of an aqueous solution of ammonia, reacting the Z-aminocyclopentene-l with an acyl chloride the acyl radical of which contains from 2 to 4 carbon atoms, oxidizing the resulting Z-diacylaminocyclopentene-l to diacylglutamic acid by treating it with excess 30% to 60% nitric acid, and treating the oxidation product with a base selected from the group consisting of alkali metal and alkaline earth metal hydroxides to produce the corresponding alkali metal or alkaline earth metal salt.

10. In a method for producing sodium glutamate, the steps comprising depolymen'zing dicyclopentadiene to cyclopentadiene by distillation, treating the monomeric cyclopentadiene with gaseous hydrogen chloride until 2- chlorocyclopentene-l is produced, converting the latter to 2-aminocyclopentene-1 by treating it with an excess of an aqueous solution of ammonia, reacting the 2- aminocyclopentene-l with acetyl chloride, oxidizing the resulting 2-diacetylaminocyclopentene-1 to diacetyl glutamic acid by treating it with an excess of 30% to 60% nitric acid, and treating the oxidation product with an aqueous solution of sodium hydroxide to produce sodium glutamate.

11. A method for making Z-diacylaminocyclopentene-l which comprises the steps of distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of hydrogen chloride and hydrogen bromide, at a temperature below about 25 C., reacting the resulting Z-halocyclopentene-l with ammonia to obtain 2-aminocyclopentene-1, and then reacting the latter with a controlled amount of an acyl chloride in which the acyl radical contains from 2 to 4 carbon atoms suflicient to produce the Z-diacylamino-cyclopentene-l.

12. A method for making 2-diacylaminocyclopentene-l which comprises the steps of distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of hydrogen chloride and hydrogen bromide, at a temperature below about 25 C., reacting the resulting 2-halocyclopen tene-l with ammonia to obtain 2-aminocyclopentene-1, and then reacting the latter with an amount of an acyl chloride in which the acyl radical contains from 2 to 4 carbon atoms suificient to produce the Z-diacyIaminm cyclopentene-l.

13. A method for producing glutamic acid which comprises the steps of distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of hydrogen chloride and hydrogen bromide, at a temperature below about 25 C., reacting the resulting 2-halocyclopentene-1 with ammonia to obtain Z-aminocyclopentene-l, reacting the latter with a controlled amount of an acyl chloride in which the acyl radical contains from 2 to 4 carbon atoms to produce 2-diacylarninocyclopentene-1, and oxidizing the diacylated product to glutamic acid.

14. A method for making 2-diacyl glutamic acid which comprises the steps of distilling a polymer of cyclopentadiene to obtain the monomer, treating the monomeric cyclopentadiene with a gaseous hydrogen halide selected from the group consisting of hydrogen chloride and hydrogen bromide, at a temperature below about 5 C., reacting the resulting 2-halocyclopentene-1 with ammonia to obtain 2-aminocyclopentene-1, reacting the latter with an excess of an acyl chloride in which the acyl radical contains from 2 to 4 carbon atoms to produce 2-diacylamino-cyclopentene-1, and oxidizing the diacylated product with potassium permanganate and mineral acid to 2-diacy1 glutamic acid.

Wilson et a1.: Chemical Reviews, vol. 34 (1944), pp. 1, 9, 10.

Degering: Outline of Organic Nitrogen Compounds, 1945, PP- 2 397. 

1. IN A METHOD FOR PRODUCING GLUTAMIC ACID SULFATE THE STEPS COMPRISING DISTILLING A POLYMER OF CYCLOPENTADIENE TO OBTAIN THE MONOMER, TREATING THE MONOMERIC CYCLOPENTADIENE WITH A GADEOUS HYDROGEN HALIDE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN CHLORIDE AND HYDROGEN BROMIDE UNTIL THE CORRESPONDING 2-HALO-CYCLOPENTENE-1 IS PRODUCED, TREATING THE CYCLOPENTENE-1 WITH EXCESS AMMONIA TO OBTAIN 2-AMINOCYCLOPENTENE-1, REACTING THE LATTER WITH AN ACYL CHLORIDE IN WHICH THE ACYL RADICAL CONTAINS FROM 2 TO 4 CARBON ATOMS, OXIDIZING THE RESULTING 2DIACYLAMINOCYCLOPENTENE-1 TO 2-DIACYLGLUTAMIC ACID, AND HEATING THE LATTER IN THE PRESENCE OF SULFURIC ACID TO CONVERT IT TO GLUTAMIC ACID SULFATE. 